Total syntheses of naturally occurring diacetylenic spiroacetal enol ethers

Article abstract of DOI:10.1021/jo050822k

A highly stereoselective method for constructing a (2E)-methoxymethylidene- 1,6-dioxaspiro[4.5]-decane skeleton has been developed on the basis of the palladium(II)-catalyzed ring-closing reaction of the 3,4-dioxygenated-9-hydroxy- 1-nonyn-5-one derivativ

Full text of DOI:10.1021/jo050822k

Total Syntheses of Naturally Occurring Diacetylenic Spiroacetal
Enol Ethers
Naoki Miyakoshi, Daisuke Aburano, and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa
University, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received April 22, 2005
A highly stereoselective method for constructing a (2E)-methoxymethylidene-1,6-dioxaspiro[4.5]-
decane skeleton has been developed on the basis of the palladium(II)-catalyzed ring-closing reaction
of the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one derivatives as a crucial step. The newly developed
procedures could be successfully applied to the first total synthesis of five diacetylenic spiroacetal
enol ether natural products starting from commercially available (R,R)- or (S,S)-diethyl tartrate.
Introduction
A wide range of biological and pharmacological activi-
ties of the genus Artemisita have been reported with more
than 10 diacetylenic spiroacetal enol ether derivatives
being isolated from this plant family.1 Several related
natural products 1-6 are depicted in Figure 1. These
diacetylenic spiroacetal enol ethers have a common
structural feature, namely the (2E)-2-(2,4-hexadi-
ynylidene)-1,6-dioxaspiro[4.5]decane framework.1g,2 The
representative diacetylenic spiroacetal enol ether epoxide,
the so-called AL-1 (1), has been found to be a specific
inhibitor of the activation phase in hydrogen peroxide
production induced by 12-O-tetradecanoylphorbol-13-
acetate (TPA) treatment.1h,3 Thus, it was discovered that
AL-1 (1) strongly inhibits TPA-induced tumor promo-
FIGURE 1. Typical diacetylenic spiroacetal enol ethers.
* To whom correspondence should be addressed. Tel: +81-76-234-
4411. Fax: +81-76-234-4410.
tion.1h,3 The simpler 8-deisovaleryloxy congener, the so-
called AL-2 (2),4 also showed similar antitumor activities,
although they were much weaker than those of AL-1
(1).1h,3 Despite their unique structural features and
promising biological activity, no reports5 have dealt with
the total syntheses of AL-1 (1) and AL-2 (2) or any of the
other related diacetylenic spiroacetal enol ether natural
(1) For examples, see: (a) Bohlmann, F.; Herbst, P.; Arndt, C.;
Scho¨nowsky, H.; Gleinig, H. Chem. Ber. 1961, 94, 3193-3216. (b)
Bohlmann, F.; Herbst, P.; Dohrmann, I. Chem. Ber. 1963, 96, 226-
236. (c) Bohlmann, F.; Arndt, C.; Bornowski, H.; Kleine, K.-M.; Herbst,
P. Chem. Ber. 1964, 97, 1179-1192. (d) Bohlmann, F.; Burkhardt, T.;
Zdero, C. In Naturally Occurring Acetylenes; Academic Press: London,
1973. (e) Bohlmann, F.; Ates, N.; Jakupovic, J.; King, R. M.; Robinson,
H. Phytochemistry 1982, 21, 2691-2697. (f) Mart´ınez, V.; Barbera, O.;
Sa´nchez-Parareda, J.; Marco, J. A. Phytochemistry 1987, 26, 2619-
2624. (g) Marco, J. A.; Sanz, J. F.; Jakupovic, J.; Huneck, S. Tetrahe-
dron 1990, 46, 6931-6938. (h) Nakamura, Y.; Ohto, Y.; Murakami,
A.; Jiwajinda, S.; Ohigashi, H. J. Agric. Food Chem. 1998, 46, 5031-
5036.
(4) According to the IUPAC nomenclature system, (-)-AL-2 (2)
should be described as (-)-(2E,3S,4R,5R)-3,4-epoxy-2-(2,4-hexadi-
ynylidene)-1,6-dioxaspiro[4.5]decane. This numbering system is used
for the dioxaspiro compounds in this paper.
(5) For synthetic studies on total synthesis, see: (a) Toshima, H.;
Furumoto, Y.; Inamura, S.; Ichihara, A. Tetrahedron Lett. 1996, 37,
5707-5710. (b) Toshima, H.; Aramaki, H.; Furumoto, Y.; Inamura, S.;
Ichihara, A. Tetrahedron 1998, 54, 5531-5544. (c) Toshima, H.;
Aramaki, H.; Ichihara, A. Tetrahedron Lett. 1999, 40, 3587-3590.
(2) For structure determination, see: (a) Wurz, G.; Hofer, O.; Sanz-
Cervera, J. F.; Marco, J. A. Ann. Chem. 1993, 99-101. (b) Birnecker,
W.; Wallno¨fer, B.; Hofer, O.; Greger, H. Tetrahedron 1988, 44, 267-
276.
(3) Nakamura, Y.; Kawamoto, N.; Ohto, Y.; Torikai, K.; Murakami,
A.; Ohigashi, H. Cancer Lett. 1999, 140, 37-45.
10.1021/jo050822k CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/24/2005
J. Org. Chem. 2005, 70, 6045-6052
6045

Miyakoshi et al.
SCHEME 1
SCHEME 2
ylidene functionality from 4-yn-1-ones derivatives14 in
methanol under an atmosphere of CO (Scheme 2). Thus,
the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one 11 would
be expected to undergo a one-pot construction of the core
framework of the target natural products under the
conditions of Kato and Akita,10 which involve (i) activa-
tion of an alkyne moiety with a palladium(II) catalyst
resulting in the formation of the intermediate 10 (M )
LnPd(II)) and/or the hemiacetal species 10′ (M ) LnPd-
(II)),11 (ii) followed by intramolecular capture of the
transient oxonium ion species 10 by the terminal hy-
droxyl group, and/or nucleophilic attack of the hemiacetal
hydroxyl group11 at the activated triple bond of 10′, and
finally (iii) the palladium-mediated carbon monoxide
insertion reaction (conversion of 9 to 8) leading to the
1,6-dioxaspiro[4.5]decane skeleton 8 having an (E)-
alkoxycarbonylmethylidene moiety. This compound 8
would be a useful as well as common synthetic interme-
diate for further chemical elaboration resulting in the
stereoselective total synthesis of various diacetylenic
spiroacetal enol ether natural products. We describe here
the first total synthesis of five natural products,12 (-)-
AL-2 (2), (+)-5-epi-AL-2 (3), (-)-4, (+)-5, and (-)-6, from
tartrates in a stereocontrolled manner.
products except for the total synthesis of the structurally
simplest (()-6,6 the racemic 3,4-deoxygenated analogue
of AL-2 (2), which did not control the stereochemistry of
an enediyne moiety.
As part of our program7 to design a highly stereocon-
trolled total synthesis of natural products from com-
mercially available tartrate derivatives, we have focused
considerable attention on the total synthesis of a series
of diacetylenic spiroacetal enol ether natural products.
A general retrosynthetic analysis for these natural
products 1-6 is outlined in Scheme 1. We roughly
envisaged that a common basic core skeleton, the (2E)-
2-(2,4-hexadiynylidene)-1,6-dioxaspiro[4.5]decane 7 for
these natural products, might be constructed by the
metal-catalyzed acetal formation and spontaneous CO-
insertion reaction of the 1-hydroxy-8-nonyn-5-one deriva-
tives 11 with suitable hydroxyl functionalities via inter-
mediates 10 and/or 10′. The chiral key compound 11
would be derived from (R,R)- or (S,S)-diethyl tartrate by
conventional means.
Results and Discussion
AL-2 (2) was chosen as our first target natural product
from (R,R)-diethyl tartrate as a starting material. The
required alkynone derivative 20 possessing suitable
functionalities for the palladium-catalyzed ring-closing
reaction was prepared by conventional means depicted
in Scheme 3. The selective introduction of a pivaloyl
group on the primary alcohol moiety of the known diol
16, derived from (R,R)-diethyl tartrate according to
Saito’s procedure,13 was followed by treatment with tert-
butyldiphenylsilyl (TBDPS) chloride and then EtMgBr
to give 17 in 76% yield. Dess-Martin oxidation of 17
afforded the corresponding aldehyde, which was subse-
quently exposed to trimethylsilyldiazomethane14 and
nBuLi to provide the alkyne derivative 18 in 72% yield.
Thus, the most significant feature of this synthesis
would become transformation of 11 to the 1,6-dioxa-
spiroacetal frameworks 9 possessing a (2E)-alkoxycar-
bonylmethylidene moiety. In 2002, Yamamoto and co-
workers8 developed a novel palladium-catalyzed ring-
closing reaction9 of 4-yn-1-al derivatives 12 in methanol
resulting in the formation of cyclic acetal derivatives 13
with a (Z)-alkylidne moiety. On the other hand, Kato and
Akita10 recently reported the palladium-catalyzed forma-
tion of oxacycles 15 with (E)-methoxycarbonylmeth-
(6) (a) Bohlmann, F.; Florentz, G. Chem. Ber. 1966, 99, 990-994.
(b) Gao, Y.; Wu, W.-L.; Ye, B.; Zhou, R.; Wu, Y.-L. Tetrahedron Lett.
1996, 37, 893-896.
(7) (a) Mukai, C.; Moharram, S. M.; Kataoka, O.; Hanaoka, M. J.
Chem. Soc., Perkin Trans. 1 1995, 2849-2854. (b) Mukai, C.; Mohar-
ram, S. M.; Hanaoka, M. Tetrahedron Lett. 1997, 38, 2511-2512. (c)
Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org.
Chem. 1997, 62, 8095-8103. (d) Mukai, C.; Miyakoshi, N.; Hanaoka,
M. J. Org. Chem. 2001, 66, 5875-5880.
(10) (a) Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002,
43, 4915-4917. (b) Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett.
2002, 43, 6587-6590.
(11) Yamamoto suggested the intermediacy of the hemiacetal species
for the palladium(II)-catalyzed formation of oxacycles from the carbon-
tethered acetylenic aldehydes on the basis of the 13C NMR experiments.
See ref 8.
(8) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 764-765.
(9) For similar palladium(II)-catalyzed reactions, see: (a) Utimoto,
K. Pure Appl. Chem. 1983, 54, 1845-1852. (b) Imi, K.; Imai, K.;
Utimoto, K. Tetrahedron Lett. 1987, 28, 3127-3130. (c) Fukuda, Y.;
Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816-
5819. (d) Okumoto, H.; Nishihara, S.; Nakagawa, H.; Suzuki, A. Synlett
2000, 217-218.
(12) Part of this work was published as a preliminary communica-
tion: Miyakoshi, N.; Mukai, C. Org. Lett. 2003, 5, 2335-2338.
(13) Saito, S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996,
231-233.
(14) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107-108.
6046 J. Org. Chem., Vol. 70, No. 15, 2005

Total Syntheses of Diacetylenic Spiroacetal Enol Ethers
SCHEME 3a
FIGURE 2. Stereoselective formation of 22.
selective manner. Increasing the amounts of PdCl2-
(MeCN)2 from 5 to 50 mol % resulted in the exclusive
formation of 23,16 which was converted into the dihydro-
pyran derivative 24 in 59% overall yield from 20 by acid
treatment. 2,6-Dichloroquinone and R-naphthoquinone
were used as an oxidant instead of p-benzoquinone, but
the major product was again the tetrahydropyran deriva-
tive 23. Use of other palladium(II) catalysts such as
PdCl2, Pd(OAc)2, PdCl2(PPh3)2, and PdCl2(C6H5CN)2 was
fruitless for this transformation and provided results
similar to those for PdCl2(MeCN)2 in most cases or no
reaction in some cases. The preferential formation of 23
over 22 was tentatively rationalized in terms of the Lewis
acidic property of the palladium(II) catalyst,8 which might
have catalyzed acetalization prior to activation of the
triple bond. Finally, we found that, by using a catalytic
amount of palladium(0) catalyst and excess amounts of
p-benzoquinone, in which only a minimal amount of the
active palladium(II) catalyst would be present in the
reaction vessel, we were able to retard the formation of
undesired acetal 23. In fact, The primary hydroxyl
compound 21was submitted to 5 mol % of Pd2(dba)3‚
CHCl3 and 20 equiv of p-benzoquinone in methanol under
a carbon monoxide atmosphere at room temperature to
produce the desired 22 in 41% yield as the sole product.17
No significant improvement of the chemical yield of 22
(ethyl and isopropyl esters instead of the methyl ester)
a Reaction conditions: (a) PivCl, Et3N, CH2Cl2, -78 °C; (b)
TBDPSCl, imid, DMF, 50 °C; (c) EtMgBr, Et2O rt (76%); (d) Dess-
Martin oxidation, CH2Cl2, 0 °C to rt; (e) TMSCHN2, nBuLi, THF,
-78 °C (72%); (f) PPTS, MeOH, rt (75%); (g) (i) Dess-Martin
oxidation, CH2Cl2, 0 °C to rt, (ii) TBDMSO(CH2)4MgI, Et2O-
CH2Cl2, -78°C, (iii) Dess-Martin oxidation, CH2Cl2, 0 °C to rt
(74%).
SCHEME 4a
a Reaction conditions: (a) p-TsOH, THF-H2O, rt; (b) Pd2(dba)3‚
CHCl3 (5 mol %), p-benzoquinone (20 equiv), 1 atm of CO, MeOH,
rt (41% from 20); (c) CSA, MS 4Å, THF, rt (59% from 20).
i
was observed when bulkier alcohols (EtOH and PrOH)
t
were used as a solvent. In addition, BuOH gave an
intractable mixture.
A selective desilylation of the primary silyl ether of 18
was realized by treatment with pyridinium p-toluene-
sulfonate (PPTS) in methanol to furnish 19 in 75% yield.
Transformation of 19 into the required 20 was ac-
complished as follows. Oxidation of 19 with Dess-Martin
periodinane (DMP) gave the aldehyde, which was reacted
with 4-(tert-butyldimethylsiloxy)butylmagnesium io-
dide.15 The resulting adduct was oxidized by DMP to give
the alkynone 20 in 74% yield.
The crucial transformation of 20 into the (2E)-2-
(methoxycarbonylmethylidene)-1,6-dioxaspiro[4.5]-
decane framework was investigated. A selective de-
silylation of the primary silyl ether of 20 was carried out
using p-toluenesulfonic acid (p-TsOH) in THF at room
temperature to afford the corresponding primary alcohol
21 (Scheme 4). According to Kato and Akita’s procedure,10
21 was exposed to 5 mol % of PdCl2(MeCN)2 in methanol
in the presence of p-benzoquinone as an oxidant under
an atmosphere of CO to furnish the desired spiroacetal
enol ether derivative 22 along with the tetrahydropyran
derivative 23, both in low yields. The ratio of 22 to 23
was inconsistently changed. Therefore, we needed reli-
able conditions which would consistently provide 22 in a
Exclusive formation of 22, the (5R)-isomer, might be
tentatively interpreted by the mechanism proposed by
Kato and Akita (Figure 2).10 Activation of an alkyne
moiety with the palladium(II) catalyst would be followed
by an attack of the oxygen atom of the carbonyl func-
tionality to produce the transient five-membered oxonium
intermediate A (10). Intramolecular capture of the re-
sulting oxonium ion species by the terminal hydroxyl
group would predominantly occur from the face opposite
the C4-benzyloxy functionality to avoid a nonbonding
interaction leading to the exclusive construction of 22
with the (5R)-stereochemistry. We could now synthesize
the (2E)-2-(methoxycarbonylmethylidene)-1,6-dioxaspiro-
[4.5]decane framework with suitable oxygen functional-
ities, in which all of the stereogenic centers of the first
target natural product, (-)-AL-2 (2), were constructed in
a stereocontrolled manner.
Our next efforts focused on the completion of the first
total synthesis of (-)-AL-2 (2). The dioxaspiro compound
22 was reduced with diisobutylaluminum hydride (DIBAL-
(16) A mixture of two diastereoisomers was obtained.
(17) The structure of 22 was elucidated by spectral evidence. In
particular, NOE experiments revealed no enhancement between the
vinylic proton and H-3 or between H-4 and H-10. In the 4-related
(4R,5S)-compounds, an enhancement between H-4 and H-10 was
observed in the NOE experiments.1g,5
(15) CH2Cl2 was used as a solvent instead of THF or Et2O. See:
Heintzelman, G. R.; Fang, W.-K.; Keen, S. P.; Wallace, G. A.; Wienreb,
S. M. J. Am. Chem. Soc. 2001, 123, 8851-8853.
J. Org. Chem, Vol. 70, No. 15, 2005 6047

Miyakoshi et al.
SCHEME 5a
SCHEME 6a
a Reaction conditions: (a) DIBAL-H, CH2Cl2, -78 °C (92%); (b)
MnO2, CH2Cl2, rt; (c) TMSCHN2, nBuLi, THF, -78 °C (90%); (d)
TBAF, THF, rt (94%); (e) 1-propynyl iodide, CuI, pyrrolidine, rt
(67%).
a Reaction conditions: (a) DIBAL-H, CH2Cl2, -78 °C; (b) LiDBB,
THF, -78 °C (72%); (c) MnO2, CH2Cl2, rt; (d) TMSCHN2, nBuLi,
THF, -78 °C (84%); (e) BzCl, pyridine, rt; (f) TBAF, THF, rt (95%);
(g) 1-propynyl iodide, CuI, pyrrolidine, rt (60%); (h) MsCl, Et3N,
CH2Cl2, rt; (i) K2CO3, MeOH, rt (79%).
H) to give the allyl alcohol derivative 25 in 92% yield,
which was subsequently oxidized with manganese dioxide
and then treated with trimethylsilyldiazomethane14 and
nBuLi to afford the enyne derivative 26 in 90% yield
(Scheme 5). Introduction of a propyne appendage at the
triple bond terminus of 26 under several conditions was
unsuccessful, presumably because of the bulkiness of the
silyl protecting group on the C3-hydroxyl moiety. Thus,
desilylation of 26 with tetrabutylammonium fluoride
(TBAF) furnished the hydroxyl compound 27, which was
exposed to the coupling reaction with 1-propynyl iodide
in the presence of copper(I) iodide in pyrrolidine18 at room
temperature to produce the enediyne derivative 28 in
67% yield. The final stage for completing the total
synthesis of AL-2 (2) was debenzylation and epoxy
formation. However, it turned out that debenzylation of
28 under various conditions led to the formation of an
intractable mixture, presumably due to the instability
of the enediyne moiety. Protection of the C3-hydroxyl
group of 28 was also found to be ineffective for the
debenzylation reaction.
On the basis of these unfavorable preliminary results,
two considerations became apparent. Namely, (i) to
complete the transformation of 22 into the first target
natural product, AL-2 (2), removal of the bulky silyl
group on the C3-hydroxyl functionality, prior to introduc-
tion of the terminal propyne moiety, was essential, and
(ii) the benzyl group on the C4-hydroxyl group had to be
changed to a suitable protecting group before construct-
ing the enediyne moiety. With these considerations in
mind, DIBAL-H reduction of 22 was followed by deben-
zylation with lithium di-tert-butylbiphenylide (LiDBB)19
in THF at -78 °C to furnish the diol 29 in 72% yield
(Scheme 6). A selective oxidation of the allyl alcohol
moiety of 29 with manganese dioxide gave the aldehyde,
which was converted into the enyne derivative 30 in 84%
yield by the procedure described for the preparation of
26. Introduction of a benzoyl group on the C3-hydroxyl
group of 30 and desilylation under conventional condi-
tions afforded 31 in 95% yield. According to the procedure
developed for conversion of 27 into 28, the enediyne
compound 32 (60%) was easily prepared from the enyne
derivative 31. The final phase of the first total synthesis
of AL-2 (2) was the formation of the epoxide. Compound
32 was treated with mesyl chloride and triethylamine to
give the C3-mesyloxy derivative, which was subsequently
exposed to potassium carbonate in methanol to produce
(-)-AL-2 (2) in 79% yield. The synthetic (-)-AL-2 (2) was
identical to the natural compound based on their spectral
data.2b Thus, we have completed the first total synthesis
of (-)-AL-2 (2) from commercially available (R,R)-diethyl
tartrate in a stereocontrolled manner.
The specific rotation of the simplest natural product
6, a 3,4-deoxygenated analogue of AL-2 (2), was shown
to be [R]20 (0,1b indicating that either this natural
D
product must be a racemate or that racemization had
occurred during its isolation process. As aforementioned,
the total synthesis of a racemic 6 has already been
reported,6a,b but the attempt20 at preparing it as an
optically active form has not been recorded yet. Therefore,
our efforts turned to the first synthesis of optically active
compound 6 from (-)-AL-2 (2). Treatment of 2 with
dimethyl diazomalonate in the presence of rhodium(II)
acetate [Rh2(OAc)4‚2H2O]21 in refluxing toluene effected
easy deoxygenation of the epoxy functionality to give
(-)-6 in 86% yield, the spectral data of which were
identical to those of (()-6.6a,b The synthetic (-)-6 with
the (5R)-stereochemistry showed its specific rotation,
[R]29 -47.7. Thus, we have accomplished the first
D
synthesis of optically active 6 from (R,R)-diethyl tartrate
via (-)-AL-2 (2) (Scheme 7).
Birnecker et al.2b reported the following isomerization
reaction between AL-2 (2) and its C5-epimer 3 under
acidic conditions. As a matter of fact, a solution of AL-2
(2) in MeOH-Et2O (3:1) was allowed to stand in the
presence of p-TsOH at room temperature for 6 h to give
a mixture of 2 and 3 in a ratio of 2.8 to 0.2, whereas a
(20) Ohigashi and co-workers reported preparation of compound 6
from naturally occurring AL-2 (2) and ent-3 by successive reduction,
tosylation, and olefin formation reaction. However, no description
concerning to its specific rotation could be available. See ref 1h.
(21) Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984, 25, 251-
254.
(18) Alami, M.; Ferri. F. Tetrahedron Lett. 1996, 37, 2763-2766.
(19) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924-1930.
6048 J. Org. Chem., Vol. 70, No. 15, 2005

Total Syntheses of Diacetylenic Spiroacetal Enol Ethers
SCHEME 7
SCHEME 8
similar mixture of 2 and 3 (1.2:1.8) was obtained when 3
was exposed to the same acidic conditions. Furthermore,
the secondary hydroxyl compounds 33 and 34, derived
from 2 and 3, respectively, also showed a similar equili-
bration: a mixture of 33 and 34 in a ratio of 2.7 and 0.2
from 33 as well as a mixture of 33 and 34 (1:2) from 34
was obtained.22 On the basis of these literature prece-
SCHEME 9a
2b
dents,
we expected that acid treatment of AL-2 (2)
would provide its epimer 3 in a straightforward manner.
Thus, AL-2 (2) was treated with p-TsOH in MeOH-Et2O
at room temperature. However, the desired 3 could not
be isolated from the reaction mixture, and an intractable
mixture was obtained instead. Several acidic conditions
produced by changing the solvent, the acid involving
Lewis acids, and the reaction temperature were exam-
ined, but no improvement could be accomplished. There-
fore, we next searched for an alternative method for the
synthesis of C5-epi-AL-2 (3) as well as other natural
products 4 and 6, both of which would be derived via
compound 3.
Because our next target natural products, involving not
only the C5-epi-AL-2 (3) but also 3,4-dioxygenated natural
products 4 and 5, have the (5S)-configuration in common,
we conceived the utilization of (S,S)-diethyl tartrate as
a starting material by taking advantage of newly devel-
oped procedures for the synthesis of (-)-AL-2 (2). Thus,
ent-30, derived from (S,S)-diethyl tartrate according to
the aforementioned procedure, was converted into the
labile endiyne derivative 35 by successive mesylation,
desilylation, and introduction of a propyne moiety. Final
epoxy formation of 35 leading to C5-epi-AL-2 (3) was
examined under various conditions, but only an intrac-
table mixture was obtained presumably due in large part
to the instability of the enediyne compound 35. Our
scenario was then modified by constructing an epoxy
functionality at an early stage. Thus, ent-30 was con-
verted into the mesylate, which was subsequently treated
with TBAF at room temperature to give the labile
4-hydroxyl-3-mesyloxy derivative. No epoxy formation at
lower temperature (room temperature) could be realized.
Therefore, the resulting reaction mixture in THF in the
presence of fluoride anion was directly heated under
reflux to afford the desired expoxide 36 in a quantitative
yield. Introduction of the terminal propyne residue under
the copper(I) iodide-catalyzed conditions as depicted in
the preparation of 32 from 31 (Scheme 6) was trouble-
some due to the formation of considerable amounts of
inseparable dimerized products. After searching for
several copper-free conditions, the Sonogashira-type
conditions23 were found to be suitable for this transfor-
mation. Indeed, 36 was exposed to [(allyl)PdCl]2 and tri-
(tert-butyl)phosphine in DMF23 at room temperature in
a Reaction conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C; (b) TBAF,
THF, rt to reflux (quant); (c) 1-propynyl iodide, [(allyl)PdCl]2,
tBu3P, Cs2CO3, DMF, rt (78%); (d) (i) AcOH, Cs2CO3, DMF, 80 °C,
then Ac2O, DMAP, DMF, 0 °C, (ii) 1-propynyl iodide, [(allyl)Pd-
Cl]2, tBu3P, Cs2CO3, DMF, rt (58%); (e) (i) isovaleric acid, Cs2CO3,
t
DMF, 80 °C, (ii) 1-propynyl iodide, [(allyl)PdCl]2, Bu3P, Cs2CO3,
DMF, rt (64%).
the presence of cesium carbonate to produce (+)-3 in 78%
overall yield, which was identical to the natural com-
pound.2b The ring-opening reaction of an epoxy function-
ality of 36 by nucleophiles would be expected to occur at
the C3-position in a highly regioselective manner based
on the literature precedents (e.g., conversion of 2 and 3
to 33 and 34 in Scheme 8).24 Thus, the ring-opening of
the epoxy moiety of 36 with cesium acetate25 was followed
by acetylation furnishing the corresponding diacetate,
which was subsequently exposed to the coupling condi-
tions with 1-propynyl iodide to provide (-)-4 in 58%
overall yield. Similarly, treatment of 36 with cesium
isovalerate in DMF at 80 °C effected the regioselective
cleavage of an epoxy group to give the 4-hydroxy-3-
isovaleroxy derivative, which was then transformed to
the target (+)-5 in 64% yield (Scheme 9). Both synthetic
natural products, 4 and 5, were identical to the corre-
sponding natural products2a based on a comparison of
their spectral data.
(24) An epoxy group of ent-3 was regioselectively cleaved at the C3-
position when treated with 10% hydrochloric acid in methanol. See
ref 1h.
(25) (a) Kuntz, H.; Kullmann, R.; Wernig, P.; Zimmer, J. Tetrahedron
Lett. 1992, 33, 1969-1972. (b) Arbelo, D. O.; Prieto, J. A. Tetrahedron
Lett. 2002, 43, 4111-4114.
(22) Ohigashi and co-workers isolated 1 mg of (+)-3 when 4.2 mg of
(-)-AL-2 (2) was exposed to the same acidic conditions. See ref 1h.
(23) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.:
Hughes, D. L. Org. Lett. 2003, 4, 4191-4194.
J. Org. Chem, Vol. 70, No. 15, 2005 6049

Miyakoshi et al.
4.9, 2.0 Hz), 4.06 (dd, 1H, J ) 10.7, 2.6 Hz), 3.88 (dd, 1H, J )
10.7, 7.3 Hz), 3.48 (ddd, 1H, J ) 7.3, 4.9, 2.6 Hz), 2.27 (d, 1H,
J ) 2.0 Hz), 1.07 (s, 9H), 0.95 (s, 9H), 0.04 (s, 6H); 13C NMR
δ 138.6, 136.1, 135.8, 133.1, 129.8, 129.7, 128.1, 127.7, 127.6,
127.4, 127.3, 82.3, 82.2, 74.1, 72.9, 63.5, 63.4, 31.6, 26.9, 26.0,
25.9, 22.6, 19.3, 18.2, 14.1, 9.4, -5.3, -5.4; FABMS m/z 581
(M+ + 1, 1.1). Anal. Calcd for C34H46O3Si2: C, 73.07; H, 8.30.
Found: C, 72.71, H, 8.57.
(2S,3S)-2-Benzyloxy-3-(tert-butyldiphenylsiloxy)-4-pen-
tyn-1-ol ((-)-19). PPTS (570 mg, 2.27 mmol) was added to a
solution of (-)-18 (1.15 g, 2.06 mmol) in MeOH (10 mL) at
room temperature, and the reaction mixture was stirred for
24 h. MeOH was evaporated off, and the residue was taken
up in AcOEt, which was washed with saturated aqueous
NaHCO3, water, and brine, dried, and concentrated to dryness.
Chromatography of the residue with hexane-AcOEt (5:1)
afforded (-)-19 (683 mg, 75%) as a colorless oil: [R]27D -5.7 (c
1.00, CHCl3); IR 3587, 3306, 2120 cm-1; 1H NMR δ 7.75-7.71
(m, 2H), 7.69-7.65 (m, 2H), 7.47-7.33 (m, 6H), 7.27-7.14 (m,
5H), 4.56 (dd, 1H, J ) 5.3, 2.0 Hz), 4.47, 4.30 (AB-q, 2H, J )
11.9 Hz), 4.01-3.82 (m, 2H), 3.52-3.47 (m, 1H), 2.37 (d, 1H,
J ) 1.7 Hz), 1.09 (s, 9H); 13C NMR δ 137.8, 136.1, 135.8, 132.8,
132.6, 130.0, 129.9, 128.4, 128.0, 127.8, 127.8, 127.6, 81.5, 81.0,
75.0, 72.7, 63.7, 61.9, 26.9, 19.2; FABMS m/z 445 (M+ + 1,
1.1). Anal. Calcd for C28H32O3Si: C, 75.63; H, 7.25. Found: C,
75.55, H, 7.26.
In summary, we have developed a highly stereoselec-
tive method for constructing the (2E)-2-methoxymeth-
ylidene-1,6-dioxaspiro[4.5]decane skeleton by the palla-
dium (II)-catalyzed ring-closing reaction of the 3,4-
dioxygenated-9-hydroxy-1-nonyn-5-one derivatives as a
crucial step. By taking advantage of the newly developed
procedures, the first total synthesis of five diacetylenic
spiroacetal enol ether natural products, AL-2 (2), C5-epi-
AL-2 (3), 4, 5, and 6 in a chiral form, has been achieved
starting from commercially available (R,R)- or (S,S)-
diethyl tartrate depending on the configuration of the
target molecules.
Experimental Section
(2S,3S)-3-Benzyloxy-4-(tert-butyldimethylsiloxy)-2-(tert-
butyldiphenylsiloxy)butan-1-ol ((-)-17). A solution of PivCl
(1.19 mL, 9.70 mmol) in CH2Cl2 (12 mL) was added to a
solution of 16 (3.00 g, 9.20 mmol), Et3N (3.67 mL, 27.6 mmol),
and DMAP (0.11 g, 0.92 mmol) in CH2Cl2 (80 mL) at -78 °C
over a period of 3 h. After being stirred for 16 h at the same
temperature, the reaction mixture was quenched by addition
of water and extracted with CH2Cl2. The extract was washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (1:1) to afford the crude alcohol. To a solution
of the crude alcohol and imidazole (1.88 g, 27.6 mmol) in DMF
(4.5 mL) was added TBDPSCl (3.56 mL, 13.8 mmol) at room
temperature. The reaction mixture was stirred at 50 °C for
42 h, quenched by addition of water, and extracted with Et2O.
The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was passed through a
short pad of silica gel with hexane-AcOEt (1:1) to afford the
crudeTBDPS-protected product. To a solution of the crudeT-
BDPS-protected product in Et2O (90 mL) was added EtMgBr
in Et2O (1.00 M, 92.0 mL, 92.0 mmol) at room temperature,
and the reaction mixture was stirred for 22 h, quenched by
addition of water, and extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to
dryness. Chromatography of the residue with hexane-AcOEt
(3S,4R)-4-Benzyloxy-9-(tert-butyldimethylsiloxy)-3-(tert-
butyldiphenylsiloxy)-1-nonyn-5-one ((+)-20). According to
the procedure described for oxidation of (-)-17, (-)-19 (146
mg, 0.33 mmol) was converted to the corresponding aldehyde.
The crude aldehyde was used directly for the next reaction. A
solution of Grignard reagent in Et2O was adjusted as follows:
4-tert-butyldimethylsiloxybutyl-1-iodide (2.00 g, 6.37 mmol) in
Et2O (8.0 mL) was added to a suspension of magnesium
powder (440 mg, 18.3 mmol) in Et2O (4.0 mL). The mixture
was vigorously stirred at room temperature for 30 min. The
Grignard reagent (0.50 M, 1.32 mL, 0.66 mmol), thus prepared,
was added to a solution of the crude aldehyde in CH2Cl2 (3.0
mL) at -78 °C. After being stirred for 20 min, the reaction
mixture was quenched by addition of saturated aqueous NH4-
Cl and extracted with Et2O. The extract was washed with
water and brine, dried, and concentrated to leave the crude
alcohol. The crude alcohol was then oxidized by DMP to afford
(10:1) afforded (-)-17 (3.94 g, 76%) as a colorless oil: [R]27
D
-18.0 (c 1.00, CHCl3); IR 3612 cm-1; 1H NMR δ 7.68-7.64 (m,
4H), 7.43-7.32 (m, 6H), 7.28-7.16 (m, 5H), 4.51, 4.36 (AB-q,
2H, J ) 11.9 Hz), 3.95-3.83 (m, 3H), 3.62-3.57 (m, 2H), 3.49
(m, 1H), 1.06 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR δ
138.5, 135.9, 135.7, 133.7, 133.3, 129.8, 129.2, 127.7, 127.6,
127.4, 81.8, 72.7, 72.6, 63.4, 62.3, 27.0, 19.3, 18.2, -5.4, -5.5;
MS m/z 564 (M+, 1.1); HRMS calcd for C33H48O4Si2 564.3091,
found 564.3095.
the title compound (102 mg, 74%) as a colorless oil: [R]28
D
1
+33.6 (c 1.00, CHCl3); IR 3306, 2122, 1716 cm-1; H NMR δ
7.75-7.66 (m, 4H), 7.43-7.24 (m, 11H), 4.71 (dd, 1H, J ) 4.9,
2.4), 4.58, 4.56 (AB-q, 2H, J ) 11.7), 3.89 (d, 1H, J ) 4.9),
3.57 (t, 2H, J ) 6.8), 2.66 (m, 1H), 2.57 (m, 1H), 2.29 (d, 1H,
J ) 2.4) 1.61-1.45 (m, 4H), 1.04 (s, 9H), 0.88 (s, 9H), 0.03 (s,
6H);13C NMR δ 208.8, 137.3, 136.1, 135.9, 132.9, 132.7, 129.9,
129.7, 128.3, 127.9, 127.9, 127.6, 127.3, 86.7, 81.1, 75.8, 73.4,
64.6, 62.9, 40.0, 32.3, 26.8, 25.9, 19.3, 18.3, -5.3; MS m/z 628
(M+ + 1, 1.4). Anal. Calcd for C38H52O4Si2: C, 72.56; H, 8.33.
Found: C, 72.20, H, 8.53.
(2E,3R,4R,5R)-4-Benzyloxy-3-(tert-butyldiphenylsiloxy)-
2-methoxycarbonylmethylidene-1,6-dioxaspiro[4.5]-
decane ((-)-22). p-TsOH was added to a solution of (+)-20
(61.0 mg, 0.10 mmol) in a combined solution of THF and H2O
(20:1, 3.0 mL) at room temperature. The reaction mixture was
stirred at the same temperature for 4 h, quenched by addition
of saturated aqueous NaHCO3, and extracted with Et2O. The
extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad
of silica gel with hexane-AcOEt (1:1) to afford the crude
alcohol. A solution of Pd2(dba)3‚CHCl3 (2.5 mg, 0.002 mmol)
in MeOH (3.5 mL) was stirred under a CO atmosphere at room
temperature for 30 min, to which a solution of the crude alcohol
and benzoquinone (217 mg, 1.94 mmol) in MeOH (1.5 mL) was
added. After being stirred for 48 h, MeOH was evaporated off
and the residue was taken up in CH2Cl2, which was succes-
sively washed with saturated aqueous Na2S2O3, saturated
aqueous NaHCO3, water, and brine, dried, and concentrated
(3S,4S)-4-Benzyloxy-5-(tert-butyldimethylsiloxy)-3-(tert-
butyldiphenylsiloxy)pent-1-yne ((-)-18). To a solution of
(-)-17 (400 mg, 0.71 mmol) in CH2Cl2 (7.0 mL) was added
Dess-Martin periodinane (DMP) (470 mg, 1.01 mmol) at 0 °C.
The reaction mixture was stirred at room temperature for 1
h, poured into a solution of sodium thiosulfate and sodium
bicarbonate (1:1), and extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to
dryness. The crude aldehyde was used directly for the next
reaction. To a solution of TMSCLi(N2) in THF (2.0 mL),
prepared from reaction of TMSCHN2 in hexane (1.50 M, 2.00
n
mL, 3.00 mmol) and BuLi in hexane (1.43 M, 1.50 mL, 2.20
mmol) at -78 °C for 30 min, was added a solution of the crude
aldehyde in THF (3.0 mL). The reaction mixture was stirred
at -78 °C for 30 min and then allowed to stand at 0 °C for 30
min, quenched by addition of water, and extracted with Et2O.
The extract was washed with water, and brine, dried, and
concentrated to dryness. Chromatography of the residue with
hexane-AcOEt (10:1) afforded (-)-18 (297 mg, 72%) as a
colorless oil: [R]25 -0.5 (c 1.00, CHCl3); IR 3306, 2120 cm-1
;
D
1H NMR δ 7.74-7.71 (m, 2H), 7.66-7.64 (m, 2H), 7.44-7.30
(m, 6H), 7.27-7.20 (m, 5H), 4.54 (s, 2H), 4.51 (dd, 1H, J )
6050 J. Org. Chem., Vol. 70, No. 15, 2005

Total Syntheses of Diacetylenic Spiroacetal Enol Ethers
to dryness. Chromatography of the residue with hexane-
7.62-7.57 (m, 1H), 7.48-7.42 (m, 2H), 5.30 (s, 1H), 5.22 (m,
1H), 4.80 (d, 1H, J ) 9.9 Hz), 3.98-3.78 (m, 2H), 3.04-3.01
(m, 2H) 1.85-1.60(m, 6H); 13C NMR δ 169.3, 164.9, 133.6,
129.9, 128.9, 128.6, 109.6, 83.9, 80.3, 79.6, 78.9, 74.5, 62.7, 27.6,
24.4, 18.5; MS m/z 314 (M+, 2.8); HRMS calcd for C18H18O5
314.1154, found 314.1157.
AcOEt (30:1) afforded (-)-22 (23.0 mg, 41%) as a colorless oil:
1
[R]26 -75.0 (c 1.00, CHCl3); IR 1707, 1659 cm-1; H NMR δ
D
7.95-7.93 (m, 2H), 7.69-7.66 (m, 2H), 7.49-7.32 (m, 6H),
7.24-7.19 (m, 3H), 6.97-6.95 (m, 2H), 5.42(s, 1H), 5.39 (s, 1H),
3.98 (m, 1H), 3.77 (m, 1H), 3.70 (s, 2H), 3.61 (s, 1H), 3.31 (s,
3H), 1.95-1.56 (m, 6H), 1.03 (s, 9H); 13C NMR δ 173.6, 167.0,
137.6, 136.6, 136.0, 133.9, 133.3, 129.9, 129.4, 128.1, 127.7,
127.4, 127.2, 127.0, 110.8, 93.7, 86.1, 73.6, 71.0, 62.4, 50.6, 28.7,
26.7, 24.8, 19.4, 19.1; FABMS m/z 573 (M+ + 1, 1.1); FAB-
HRMS calcd for C34H41O6Si 573.2672, found 573.2640.
(2E,3S,4R,5R)-3,4-Epoxy-2-(2,4-hexadiynylidene)-1,6-
dioxaspiro[4.5]decane ((-)-AL-2). MsCl (0.87 × 10-2 mL,
0.11 mmol) was added to a solution of (+)-32 (4.00 mg, 0.11 ×
10-1 mmol) and Et3N (0.28 × 10-1 mL, 0.20 mmol) in CH2Cl2
(0.50 mL) at 0 °C. After being stirred for 5 min, the reaction
mixture was quenched by addition of water and extracted with
CH2Cl2, which was washed with water and brine, dried, and
concentrated to dryness. The crude methanesulfonate was used
directly for the next reaction. K2CO3 (15.1 mg 0.11 mmol) was
added to a solution of the residue in MeOH (1.5 mL), and the
reaction mixture was stirred for 1 h. MeOH was evaporated
off, and the residue was taken up in AcOEt, which was washed
with water and brine, dried, and concentrated to dryness.
Chromatography of the residue with hexane-AcOEt (10:1)
afforded (-)-2 (2.1 mg, 79%) as a colorless oil: [R]27D -26.6 (c
(2E,3R,4R,5R)-4-Benzyloxy-2-(2,4-hexadiynylidene)-
1,6-dioxaspiro[4.5]decan-3-ol ((-)-28). CuI (1.0 mg, 0.57 ×
10-2 mmol) was added to a solution of (+)-27 (3.3 mg, 0.11 ×
10-1 mmol) and 1-propynyl iodide (0.20 × 10-1 mL, 0.19 mmol)
in pyrrolidine (1.0 mL) at room temperature. The reaction
mixture was stirred for 1.5 h, diluted with water, and extracted
with Et2O. The extract was washed with water, and brine,
dried, and concentrated to dryness. Chromatography of the
residue with hexane-AcOEt (7:2) afforded (+)-28 (2.50 mg,
67%) as a colorless oil: [R]27D -126.8 (c 0.36, CHCl3); IR 3690,
2253, 2142, 1649 cm-1; 1H NMR δ 7.38-7.25 (m, 5H), 5.17 (br-
s, 1H), 4.76 (d, 1H, J ) 9.8 Hz), 4.73, 4.53 (AB-q, 2H, J ) 12.0
Hz), 3.91-3.71 (m, 2H), 2.91 (d, 1H, J ) 9.8 Hz), 2.00 (m, 1H),
1.98 (d, 3H, J ) 1.0 Hz), 1.75-1.60 (m, 5H); 13C NMR δ 171.5,
137.3, 128.5, 128.0, 127.7, 110.4, 85.7, 83.4, 79.8, 73.6, 71.9,
70.2, 64.9, 62.7, 28.0, 24.7, 18.6, 4.5; FABMS m/z 339 (M+, 9.5);
FABHRMS calcd for C21H23O4 339.1596, found 339.1595.
0.14 CHCl3) (lit.2b [R]20 -14 (c 0.5, CHCl3)); IR 2143, 1655
D
1
cm-1; H NMR δ 5.18 (s, 1H), 4.29 (d, 1H, J ) 2.5 Hz), 3.87
(dt, 1H, J ) 3.0, 11.2 Hz), 3.80 (d, 1H, J ) 2.5 Hz), 3.77 (m,
1H), 1.99 (s, 1H), 1.93-1.90 (m, 1H), 1.79-1.58 (m, 5H); 13C
NMR δ 164.9, 105.9, 85.9, 79.6, 69.8, 63.2, 60.0, 51.9, 28.8,
24.8, 18.7, 4.6; MS m/z 230 (M+, 13.8); HRMS calcd for
C14H14O3 230.0943, found 230.0945.
(2E,5R)-2-(2,4-Hexadiynylidene)-1,6-dioxaspiro[4.5]dec-
3-ene ((-)-6). A solution of dimethyl diazomalonate (19.0 mg,
0.12 mmol) in toluene (0.5 mL) was added to a mixture of Rh2-
(OAc)4‚2H2O (1.20 mg, 0.24 × 10-2 mmol) and (-)-AL-2 (5.6
mg, 0.24 × 10-1 mmol) in toluene (2.0 mL) at room tempera-
ture. The reaction mixture was refluxed for 1 h. Toluene was
evaporated off, and the residue was chromatographed with
hexane-AcOEt (20:1) to afford (-)-6 (4.5 mg, 86%) as a
colorless oil: [R]29 -47.7 (c 0.09 Et2O) (lit.1b [R]20 0 (Et2O));
(2E,3R,4R,5R)-3-(tert-Butyldiphenylsiloxy)-2-(2-hydrox-
yethylidene)-1,6-dioxaspiro[4.5]decan-4-ol ((-)-29). Ac-
cording to the procedure described for reduction of (-)-22, (-)-
15 (79.0 mg, 0.14 mmol) was converted to the corresponding
crude alcohol. A solution of lithium tert-butylbiphenylide in
THF was prepared as follows: lithium (20.0 mg, 2.85 mmol)
was added to a solution of p,p′-di-tert-butylbiphenyl (620 mg,
2.38 mmol) in THF (14 mL) at room temperature. The mixture
was vigorously stirred at room temperature until the dark
green radical anion was developed, at which time the reaction
mixture was cooled in ice bath. Stirring was continued at 0
°C for 4 h. A solution of LiDBB in THF, thus prepared, was
added to a solution of the crude alcohol in THF (3.0 mL) at
-78 °C until the reaction mixture turned to deep green. After
being stirred for 10 min at -78 °C, the reaction mixture was
quenched by addition of water and extracted with AcOEt. The
extract was washed with water and brine, dried, and concen-
trated to dryness. Chromatography of the residue with hexane-
AcOEt (1:1) afforded (-)-29 (45.0 mg, 72%) as colorless
needles: mp 178.5-179.5 °C (hexane-AcOEt); [R]24D -71.6 (c
D
D
IR 2190 2150 cm-1; H NMR δ 6.66 (d, 1H, J ) 5.9 Hz), 6.22
(dd, 1H, J ) 5.9, 2.0 Hz), 4.97 (br-s, 1H), 3.98 (m, 1H), 3.82
(m, 1H), 1.98 (d, 3H, J ) 1.0 Hz), 1.95-1.86 (m, 1H), 1.81-
1.59 (m, 5H); 13C NMR δ 169.8, 138.4, 125.1, 112.7, 79.8, 79.6,
76.2, 71.6, 65.0, 64.3, 32.5, 24.4, 19.2, 4.7; MS m/z 214 (M+,
9.0); HRMS calcd for C14H14O3 214.0994, found 214.0991.
1
(2E,3S,4R,5S)-3,4-Epoxy-2-(2,4-hexadiynylidene)-1,6-
dioxaspiro[4.5]decane ((+)-3). To a solution of (+)-36 (1.7
mg, 0.89 × 10-2 mmol), (allylPdCl)2 (1.0 mg, 0.27 × 10-2 mmol),
tBu3P (2.2 mg, 0.11 × 10-2 mmol), and Cs2CO3 (29.0 mg, 0.89
× 10-1 mmol) in DMF (1.5 mL) was added 1-propynyl iodide
(14.8 mg, 0.89 × 10-1 mmol) at room temperature. After being
stirred for 0.5 h, the reaction mixture was quenched by
addition of water and extracted with Et2O, which was washed
with water and brine, dried, and concentrated to dryness.
Chromatography of the residue with hexane-AcOEt (5:1)
1
0.74, THF); IR 3311, 3177, 1699 cm-1; H NMR δ 7.80-7.74
(4H, m) 7.48-7.41 (m, 6H), 5.25 (dt, 1H, J ) 1.3, 7.9 Hz), 4.58
(br s, 1H), 4.14-3.68(m, 5H), 1.85-1.60 (m, 6H), 1.06 (s, 9H).;
13C NMR δ 158.5, 136.0, 136.0, 133.3, 132.9, 130.2, 130.0,
128.0, 127.8, 107.3, 102.0, 80.9, 62.2, 58.6, 28.2, 26.8, 24.9, 19.4,
19.0; MS m/z 454 (M+, 0.1); HRMS calcd for C26H34O5Si
454.2175, found 454.2174.
afforded (+)-3 (1.4 mg, 68%) as a colorless oil: [R]26 +245.8
D
(c 0.01, CHCl3) (lit.2b [R]20D +259 (c 0.5, CHCl3)); IR 2146, 1653
cm-1; 1H NMR δ 5.14 (q, 1H, J ) 1.0 Hz), 4.28 (d, 1H, J ) 3.0
Hz), 3.90-3.87 (m, 2H), 3.79 (d, 1H, J ) 3.0 Hz), 1.98 (d, 1H,
J ) 1.0 Hz), 1.85-1.60 (m, 6H); 13C NMR δ 163.6, 105.9, 85.4,
79.7, 69.7, 64.7, 58.9, 52.2, 30.7, 24.4, 18.0; MS m/z 230 (M+,
2); HRMS calcd for C14H14O5 230.0943, found 230.0945.
(2E,3R,4R,5R)-4-Benzoyloxy-2-propynylidene-1,6-
dioxaspiro[4.5]decan-3-ol ((+)-31). BzCl (0.05 mL, 0.42
mmol) was added to a solution of (-)-30 (6.20 mg, 0.14 × 10-1
mmol) in pyridine (1.5 mL) at room temperature. After being
stirred for 20 min, the reaction mixture was quenched by
addition of water and extracted with Et2O, which was washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (30:1) to afford the crude benzoate. To a
solution of crude benzoxylate in THF (6.0 mL) was added
TBAF‚xH2O (10.0 mg), and the reaction mixture was stirred
for 4 h at room temperature, quenched by addition of water,
and extracted with Et2O. The extract was washed with water
and brine, dried, and concentrated to dryness. Chromatogra-
phy of the residue with hexane-AcOEt (2:1) afforded (+)-31
(4.10 mg, 95%) as a colorless oil: [R]26D +38.4 (c 0.37, CHCl3);
IR 3308, 2108, 1728, 1657 cm-1; 1H NMR δ 8.03-7.99 (m, 2H),
(2E,3R,4R,5S)-3,4-Diacetoxy-2-(2,4-hexadiynylidene)-
1,6-dioxaspiro[4.5]decane ((-)-4). A mixture of Cs2CO3 (52.0
mg, 0.16 mmol) and acetic acid (9.6 mg, 0.16 mmol) in DMF
(1.0 mL) was heated at 80 °C for 1 h. The reaction mixture
was cooled to room temperature, to which a solution of (+)-36
(3.0 mg, 0.16 × 10-1 mmol) in DMF (0.7 mL) was added. The
mixture was heated at 80 °C for 3 h. Ac2O (0.15 × 10-1 mL,
0.16 mmol) and DMAP (19.5 mg, 0.16 mmol) were added to
the mixture at 0 °C, which was then stirred for 5 min,
quenched by addition of water, and extracted with Et2O. The
extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad
J. Org. Chem, Vol. 70, No. 15, 2005 6051

Miyakoshi et al.
of silica gel with hexane-AcOEt (5:1) to afford the crude
diacetate. The crude diacetate was exposed to the procedure
described for cross coupling of (+)-36 to afford the title
compound (3.10 mg, 58%) as a colorless oil: [R]23D -0.9 (c 0.05,
[R]24D +68 (c 2.28, CHCl3)); IR 2145, 1745, 1653 cm-1; 1H NMR
δ 5.99 (dd, 1H, J ) 7.3, 2.3 Hz), 5.11 (br-s, 1H), 3.86-3.82 (m,
2H), 2.40 (dd, 1H, J ) 15.6, 6.8 Hz), 2.31 (dd, 1H, J ) 15.6,
7.3 Hz), 2.19 (m, 1H), 1.95 (br-s, 3H), 1.90-1.60 (m, 6H), 1.01
(d, 3H, J ) 6.6 Hz), 1.00 (d, 3H, J ) 6.6 Hz); 13C NMR δ 172.7,
164.6, 104.0, 83.4, 80.0, 79.7, 78.0, 76.0, 68.7, 64.6, 63.1, 42.7,
30.0, 25.4, 24.3, 22.6, 22.5, 18.6, 4.6; MS m/z 332 (M+, 21);
HRMS calcd for C18H20O6 332.1624, found 332.1622.
CHCl3) (lit.1g [R]24 -1 (c 1.16, CHCl3)); IR 2145, 1745, 1653
D
cm-1; 1H NMR δ 6.25 (dd, 1H, J ) 7.9, 0.7 Hz), 5.17-5.14 (m,
2H), 3.83 (m, 1H), 2.16 (s, 3H), 2.15 (s, 3H), 1.96 (s, 3H), 1.80-
1.60 (m, 6H); 13C NMR δ 170.4, 169.9, 164.1, 104.2, 83.8, 80.3,
78.4, 78.1, 73.1, 68.5, 64.5, 63.1, 30.6, 24.1, 20.9, 20.4, 18.7,
4.7; MS m/z 332 (M+, 30); HRMS calcd for C18H20O6 332.1260,
found 332.1247.
Acknowledgment. This work was supported in part
by a Grant-in Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan, for which we are also thankful.
(2E,3R,4R,5S)-2-(2,4-Hexadiynylidene)-3-isovaleryloxy-
1,6-dioxaspiro[4.5]decan-4-ol ((+)-5). A mixture of Cs2CO3
(52.0 mg, 0.16 mmol) and isovarelic acid (16.3 mg, 0.16 mmol)
in DMF (1.0 mL) was heated at 80°C for 1 h. The reaction
mixture was cooled to room temperature, to which a solution
of (+)-36 (3.0 mg, 0.16 × 10-1 mmol) in DMF (0.7 mL) was
added. The mixture was heated at 80 °C for 3 h, quenched by
addition of water, and extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to
dryness. The residue was passed through a short pad of silica
gel with hexane-AcOEt (5:1) to afford the crude isovalerate.
The crude isovalerate was exposed to the procedure described
for cross-coupling of (+)-36 to afford the title compound (3.60
mg, 68%) as a colorless oil: [R]24D +68.3 (c 0.04, CHCl3) (lit.1g
Supporting Information Available: 1H and 13C NMR
spectra for compounds (-)-2, (+)-3, (-)-4, (+)-5, (-)-6, (-)-17,
(-)-22, (+)-24, (-)-27, (-)-28, (-)-29, (-)-30, (+)-31, (+)-32,
and (+)-36; preparation and characterization data for com-
pounds (+)-24, (-)-25, (-)-26, (-)-27, (-)-30, (+)-32, and (+)-
36; characterization data for compounds (+)-17, (+)-18, (+)-
19, (-)-20, (+)-22, (+)-29, and (+)-30. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050822K
6052 J. Org. Chem., Vol. 70, No. 15, 2005